Effect of Microgravity on Drug Responses Using Engineered Heart Tissues
微重力对工程心脏组织药物反应的影响
基本信息
- 批准号:10173394
- 负责人:
- 金额:$ 72.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-18 至 2022-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdrenergic beta-AntagonistsAffectAfrican AmericanAge-YearsAngiotensin-Converting Enzyme InhibitorsAnimal ModelAnimalsArchitectureAstronautsAtrophicBackBiologicalBiological AssayBiologyCachexiaCardiacCardiac MyocytesCardiomyopathiesCardiovascular DiseasesCardiovascular systemCarotid ArteriesCaucasiansCell AdhesionCell CommunicationCell Culture TechniquesCell physiologyCellsClassificationClinicalComplexDiseaseDoctor of PhilosophyDrug CombinationsDrug InteractionsDrug ScreeningElectrophysiology (science)Endothelial CellsEngineeringEnvironmentExposure toExtracellular MatrixFemaleFibroblastsForce of GravityGene ExpressionHeartHeart failureHispanic AmericansHispanicsHumanIn VitroIndividualInstitutesInternationalLaboratoriesMammalian CellMeasuresMechanicsMetabolicMicrogravityMicroscopicMissionMitochondriaModelingMolecularMorphologyMuscular AtrophyMyocardiumNormal CellOrganOrganoidsPatientsPatternPharmaceutical PreparationsPharmacogenomicsPhasePhenotypePhysiologicalPhysiological AdaptationPhysiologyPlanet EarthPlasmidsPreventionProteinsProteomicsProtocols documentationRaceReportingResearchRiskSamplingSignal PathwaySomatic CellSpace FlightStructureTechnologyTestingTherapeuticTimeTissue EngineeringTissue MicroarrayTissue ModelTissuesTranslatingTungstenUniversitiesWeightbaseblastomere structureblood pressure reductioncardiac tissue engineeringcardiogenesiscardiovascular healthcaucasian Americancell typecohortdisease phenotypedrug candidatedrug discoverydrug testingdrug use screeningendothelial stem cell ethnic diversityextracellularhealthy volunteerheart functionhuman diseasein vitro Modelinduced pluripotent stem cellinsightinterestischemic cardiomyopathymalememberminiaturizepatient responsepreservationpreventprofessorracial diversityrecruitresponsescaffoldsecretory proteinself assemblysexspace stationspace travelspatiotemporalthree dimensional structurethree-dimensional modelingtooltranscriptome sequencingtranscriptomicstwo-dimensional
项目摘要
PROJECT SUMMARY
Tissue engineered organs or functional tissue-like ensembles contribute significantly to our understanding of
cellular niches that allow cells to migrate, develop and mature in three dimensions (3-D). Conventional two-
dimensional (2-D) mammalian cell culture does not represent the physiological environments that form the basis
for normal cell function. A 3-D environment promotes isotropic cell-cell communications, provides extracellular
guidance from structural matrix scaffolding, and allows spatiotemporal remodelling. Our specific interest is in
investigating the effects of microgravity on heart function with the use of Engineered Heart Tissues (EHTs). Since
these tissue engineering platforms support multicellular architecture from a ‘bottom-up’ approach, it is critical to
understand the mechanisms of heart development from a primordial state. Although animal models are used
widely to investigate biological responses to therapeutics, inherent differences between human and animal
biology combined with the unlikelihood of animals developing a human disease limit the ability to validate
research findings. Human induced pluripotent stem cells (hiPSCs) have emerged as an indispensable tool to
drive cells from an embryonic state to any somatic cell type. Our laboratory’s focus and expertise in generating
hiPSC-derived cardiomyocytes (hiPSC-CMs) and modelling of cardiomyopathies has yielded deeper insight into
several rare and common causes of heart failure. To maintain a tissue-specific microenvironment, dissociated
cells must be cultured in a physiologically relevant 3-D extracellular matrix (ECM). In the first phase (UG3), we
will generate hiPSC-CMs from healthy patients belonging to diverse racial groups (Caucasians, Hispanics, and
African Americans). The hiPSC-CMs will be used to fabricate our well-characterized EHT platforms, to
understand cellular mechanisms that affect cardiac function both under microgravity and earth’s gravity.
Alterations in cardiac function due to weakened heart muscles in the samples exposed to microgravity will be
matched with molecular and electrophysiological disease patterns observed in ischemic cardiomyopathy. In the
second phase (UH3), the well-characterized microgravity-induced disease phenotype will be translated on Heart
Tissue Arrays (HTA) to screen for potential drug candidates in a high-throughput manner. The proposed study
will for the first time reveal key functional and molecular differences that drive phenotypic changes in heart tissues
on EHT assemblies under influence of microgravity.
项目概要
组织工程器官或功能性类组织整体有助于我们理解
允许细胞在三维 (3-D) 上迁移、发育和成熟的细胞生态位。常规二-
三维(2-D)哺乳动物细胞培养并不代表构成基础的生理环境
为了正常的细胞功能。 3D 环境促进各向同性细胞间通讯,提供细胞外
来自结构矩阵脚手架的指导,并允许时空重塑。我们的具体兴趣在于
使用工程心脏组织 (EHT) 研究微重力对心脏功能的影响。自从
这些组织工程平台以“自下而上”的方式支持多细胞结构,这一点至关重要
从原始状态了解心脏发育的机制。虽然使用动物模型
广泛研究对治疗的生物反应以及人类和动物之间的固有差异
生物学加上动物不太可能患上人类疾病,限制了验证的能力
研究结果。人类诱导多能干细胞(hiPSC)已成为不可或缺的工具
驱动细胞从胚胎状态转变为任何体细胞类型。我们实验室在生成方面的重点和专业知识
hiPSC 衍生的心肌细胞 (hiPSC-CM) 和心肌病模型使人们对以下问题有了更深入的了解
心力衰竭的几种罕见和常见原因。为了维持组织特异性的微环境,解离
细胞必须在生理相关的 3-D 细胞外基质 (ECM) 中培养。在第一阶段(UG3),我们
将从属于不同种族群体(白人、西班牙裔和白人)的健康患者中产生 hiPSC-CM
非裔美国人)。 hiPSC-CM 将用于制造我们特性良好的 EHT 平台,以
了解在微重力和地球重力下影响心脏功能的细胞机制。
由于暴露于微重力的样品中心肌减弱而导致心脏功能的改变
与缺血性心肌病中观察到的分子和电生理疾病模式相匹配。在
第二阶段(UH3),充分表征的微重力诱发的疾病表型将在心脏上转化
组织阵列 (HTA) 以高通量方式筛选潜在的候选药物。拟议的研究
将首次揭示驱动心脏组织表型变化的关键功能和分子差异
微重力影响下的 EHT 组件。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Beth L Pruitt其他文献
Beth L Pruitt的其他文献
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{{ truncateString('Beth L Pruitt', 18)}}的其他基金
Effect of Microgravity on Drug Responses Using Engineered Heart Tissues
微重力对工程心脏组织药物反应的影响
- 批准号:
10670018 - 财政年份:2022
- 资助金额:
$ 72.06万 - 项目类别:
Predoctoral Training Program in Quantitative Mechanobiology
定量力学生物学博士前培训项目
- 批准号:
10439646 - 财政年份:2021
- 资助金额:
$ 72.06万 - 项目类别:
Predoctoral Training Program in Quantitative Mechanobiology
定量力学生物学博士前培训项目
- 批准号:
10626763 - 财政年份:2021
- 资助金额:
$ 72.06万 - 项目类别:
Predoctoral Training Program in Quantitative Mechanobiology
定量力学生物学博士前培训项目
- 批准号:
10207240 - 财政年份:2021
- 资助金额:
$ 72.06万 - 项目类别:
Effect of Microgravity on Drug Responses Using Engineered Heart Tissues
微重力对工程心脏组织药物反应的影响
- 批准号:
10239266 - 财政年份:2018
- 资助金额:
$ 72.06万 - 项目类别:
Validating engineered hiPSC-derived cardiomyocytes as model cells
验证工程化 hiPSC 衍生心肌细胞作为模型细胞
- 批准号:
9678119 - 财政年份:2016
- 资助金额:
$ 72.06万 - 项目类别:
Validating engineered hiPSC-derived cardiomyocytes as model cells
验证工程化 hiPSC 衍生心肌细胞作为模型细胞
- 批准号:
9030330 - 财政年份:2016
- 资助金额:
$ 72.06万 - 项目类别:
Force Clamp Systems for Evaluation of Mechanotransduction
用于评估机械传导的力夹系统
- 批准号:
7630592 - 财政年份:2007
- 资助金额:
$ 72.06万 - 项目类别:
Force Clamp Systems for Evaluation of Mechanotransduction
用于评估机械传导的力夹系统
- 批准号:
8147944 - 财政年份:2007
- 资助金额:
$ 72.06万 - 项目类别:
Force Clamp Systems for Evaluation of Mechanotransduction
用于评估机械传导的力夹系统
- 批准号:
7465346 - 财政年份:2007
- 资助金额:
$ 72.06万 - 项目类别: